遗传性痉挛性截瘫（HSP）是一种较为少见的家族遗传神经系统退行性变性疾病，病人的双下肢会逐渐僵直、肌无力，最后导致痉挛性瘫痪，同时伴生多种并发症。这种疾病病因复杂，目前学界还不是很清楚。而最近英美科学家称，他们研究发现了可导致某种HSP的基因变异。这为查明神经细胞退化的原因提供了重要线索，也给神经系统退行性变性疾病的治疗带来了希望。
由英国剑桥大学和美国迈阿密大学科学家领导的研究小组在最新一期《临床调查杂志》上发表文章称，位于19号染色体上reticulon 2基因突变，会导致HSP。研究小组共确认了3个可导致HSP的reticulon 2基因变异。此外他们还发现，该基因会与痉挛蛋白基因发生反应，而这种基因变异也与大多数HSP有关。
对于细胞功能的发挥来说，内质网的作用十分重要，这种细胞质内广泛分布的三维网状膜系统，在合成蛋白质、转导钙信号和调控细胞内其他成分等方面都不可或缺。而reticulon蛋白在塑造细胞内质网方面扮演着重要角色，reticulon 2基因则负责为reticulon蛋白进行遗传编码。
大多数神经退行性疾病都与神经细胞轴突退化有关，一旦轴突退化，信号则无法通过神经细胞传递，从而导致中枢神经系统信号传递的中断。该研究则提供了目前为止最为直接的证据，表明细胞内质网的缺陷会导致轴突退化。
领导该项研究的剑桥大学埃文-里德博士指出，新研究发现对于那些具有HSP家族遗传史的家庭来说十分重要，能提示这些家庭进行一些相应的遗传咨询和测试。而新的病理机制研究则为科学家们提供了一个平台，使其可以进一步研究某些神经性疾病，如HSP和多发性硬化症患者的轴突受损情况，从而为这些疾病的治疗带来新希望。(生物谷 Bioon.com)
doi:10.1172/JCI60560
PMC:
PMID:
Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12
Gladys Montenegro, Adriana P. Rebelo, James Connell, Rachel Allison, Carla Babalini, Michela D’Aloia, Pasqua Montieri, Rebecca Schüle,Hiroyuki Ishiura, Justin Price, Alleene Strickland, Michael A. Gonzalez, Lisa Baumbach-Reardon, Tine Deconinck, Jia Huang, Giorgio Bernardi,, Jeffery M. Vance,Mark T. Rogers0, Shoji Tsuji, Peter De Jonghe, Margaret A. Pericak-Vance, Ludger Schüls,, Antonio Orlacchio,, Evan Reid and Stephan Züchner,
Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules — receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) — have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.
